Sepsis constitutes a major cause of morbidity and mortality worldwide by causing life-threatening organ dysfunction, with almost 50% of patients developing acute lung injury and respiratory failure being a major cause of death. Current evidence suggests multiple processes involved in sepsis-induced acute lung injury, including endothelial barrier disruption with subsequent infiltration by immune cells. Recent studies also suggest a special role for alveolar macrophages in the progression of lung inflammation through their influence on other immune cells in the lung. However, the exact molecular mechanisms of sepsis-induced acute lung injury remain unknown and only a handful of potential interventions have been investigated. Polymerase-?-interacting protein 2 (Poldip2) is a multifunctional protein originally described over a decade ago as a 368 amino acid binding partner of DNA polymerase delta and proliferating cell nuclear antigen. Work by our lab showed that Poldip2 depletion in mice inhibited lipopolysaccharide (LPS)-induced infiltration of leukocytes into the alveolar space and strongly reduced endothelial permeability, resulting in improved mortality. Here we hypothesize that lower Poldip2 levels also affect the function of the immune cells and macrophages in particular, thus decreasing sepsis-induced lung injury. We will test our hypothesis in two specific aims. In the first aim, we will investigate the role of Poldip2 in immune cell recruitment during sepsis-induced lung injury. We will evaluate the total number of alveolar macrophages at baseline as well as the total count and percentage of pro-inflammatory and anti-inflammatory macrophages after LPS injection in Poldip2+/+ and Poldip2+/- mice. We will also assess the levels of chemokine secretion by Poldip2+/+ and Poldip2+/- macrophages and their effect on neutrophil migration. In the second aim, we will investigate the molecular mechanisms underlying the differences in macrophage activation in Poldip2 deficient mice during sepsis. We will explore classic pro-inflammatory and anti-inflammatory activation pathways in Poldip2+/+ and Poldip2+/- macrophages as well as alternative pathways previously implicated in sepsis-induced lung injury. Completion of these aims will result in a better understanding of the role of Poldip2 in sepsis-induced acute lung injury and will provide insight into new potential therapeutic targets.